Maternal and perinatal outcomes of minimally invasive fetal surgeries: experience from two reference centers in Rio de Janeiro, Brazil

ABSTRACT BACKGROUND: Concerns regarding high open surgery-related maternal morbidity have led to improvements in minimally invasive fetal surgeries. OBJECTIVE: To analyze the perinatal and maternal outcomes of minimally invasive fetal surgery performed in Rio de Janeiro, Brazil. DESIGN AND SETTING: Retrospective cohort study conducted in two tertiary reference centers. METHODS: This retrospective descriptive study was conducted using medical records from 2011 to 2019. The outcomes included maternal and pregnancy complications, neonatal morbidity, and mortality from the intrauterine period to hospital discharge. RESULTS: Fifty mothers and 70 fetuses were included in this study. The pathologies included twin-twin transfusion syndrome, congenital diaphragmatic hernia, myelomeningocele, lower urinary tract obstruction, pleural effusion, congenital upper airway obstruction syndrome, and amniotic band syndrome. Regarding maternal complications, 8% had anesthetic complications, 12% had infectious complications, and 6% required blood transfusions. The mean gestational age at surgery was 25 weeks, the mean gestational age at delivery was 33 weeks, 83% of fetuses undergoing surgery were born alive, and 69% were discharged from the neonatal intensive care unit. CONCLUSION: Despite the small sample size, we demonstrated that minimally invasive fetal surgeries are safe for pregnant women. Perinatal mortality and prematurity rates in this study were comparable to those previously. Prematurity remains the most significant problem associated with fetal surgery.


INTRODUCTION
[3] Fetal therapy has seen significant advancements in recent decades, and ultrasound has made the approach to fetal procedures safer owing to the availability of real-time guidance. 1,2,4In the early 1980s, open surgical treatments were started 5,6 , but concerns about the high maternal morbidity rates related to open surgeries have led to the search for less invasive alternatives. 7The increasing popularity of videoendoscopic surgery in the 1990s, combined with recent experience in fetoscopy, introduced the concept of endoscopic or minimally invasive fetal surgery 4 , which is under continuous development and improvement. 8 Brazil, one of the first fetal endoscopic surgeries was fetoscopy for the laser treatment of twin-twin transfusion syndrome (TTTS), which was performed in 2001. 9,10Since then, several surgical techniques for fetal surgeries, both minimally invasive and open surgeries, specifically for myelomeningocele, have been performed. 10Currently, few groups have performed percutaneous endoscopic fetal surgery for the treatment of myelomeningocele; Brazilian and German researchers have pioneered advances in performing this technique.][12][13][14]

OBJECTIVE
This article describes maternal and perinatal outcomes of minimally invasive fetal surgeries performed at two fetal medicine referral centers in Rio de Janeiro, Brazil.

METHODS
This retrospective study included all pregnant women who underwent delivery and minimally invasive fetal surgery between 2011 and 2019 at the Instituto Fernandes Figueira/Fiocruz (IFF/Fiocruz) and Clínica Perinatal, which are both referral centers for maternal-fetal medicine in Rio de Janeiro, Brazil.Clinical data and outcomes were exclusively assessed by reviewing medical records from the prenatal period to hospital discharge.This study was approved by the local institutional ethics committee under number 27452719.5.0000.5269, in accordance with the National Health Council resolution 466/12.
Outcomes included maternal and obstetric complications, neonatal morbidity, and fetal and neonatal mortality from the intrauterine period to hospital discharge.Maternal complications included anesthetic complications, infectious complications, need for blood transfusion, and admission to intensive care unit.Preterm labor, preterm delivery, chorioamnionitis, and preterm premature rupture of ovular membranes (PPROM) were considered pregnancy complications.Neonatal morbidities were defined as findings of brain injury on ultrasonography, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neonatal infection, need for ventilatory support, admission to the neonatal intensive care unit (NICU), or length of stay in the NICU.
Cerebral injuries were detected using cranial ultrasound in neonates, and they were classified as mild to severe intraventricular hemorrhages 15 or as mild to severe periventricular leukomalacia. 16ROP was classified into five stages based on the International Classification of Retinopathy of Prematurity. 17BPD was defined for newborns under 32 weeks of oxygen therapy > 21% for at least 28 days after 36 weeks of post-menstrual age or discharge to home, whichever came first, or for newborns aged ≥ 32 weeks, oxygen therapy for > 28 days but < 56 days postnatal age or discharge to home, whichever came first. 18NEC diagnosis was based on clinical signs and symptoms and radiological findings, surgically confirmed in some cases. 19Neonatal infections confirmed via laboratory testing were considered owing to the difficulty of classifying neonatal sepsis based on medical records.
Statistical analyses were performed using SPSS software version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).Frequency measures were used for categorical variables and means and standard deviations were used for numerical variables.

RESULTS
Seventy-five surgeries were performed between 2011 and 2019.
Patients who were followed up and gave birth in the research units were included, totaling 50 patients (8 at IFF/Fiocruz and 42 at Perinatal).Twenty patients had multiple pregnancies; the total of fetus was 70.Pathologies seen were as follows: 18 (36%) patients with TTTS, with or without fetal growth restriction; 12 (24%) with congenital diaphragmatic hernia (CDH); 9 (18%) with myelomeningocele (MMC); 4 (8%) with lower urinary tract obstruction; 4 (8%) with pleural effusion; 2 (4%) with congenital high airway obstruction syndrome (CHAOS); and 1 (2%) with amniotic band syndrome.The outcomes of all pathologies are described together, and for discussion purposes, the pathologies with the highest incidence were analyzed separately (TTTS, CDH, and MMC).One case each of CHAOS and CDH occurred in a woman with multiple pregnancies.Table 1 presents the baseline characteristics of the study population.

Surgical variables
The mean gestational age on the day of surgery was 25 weeks (range, 16-32 weeks), being 21 weeks (17-25 weeks) in the TTTS

Maternal complications
Concerning maternal complications, four (8%) patients had anesthetic complications, three (6%) had post-spinal anesthesia headaches, and one (2%) had decreased oxygen saturation and required macronebulization, which quickly improved their clinical condition.Six (12%) patients had infectious complications or sepsis: two (4%) were due to urinary tract infection treated with antibiotics, two (4%) were diagnosed with appendicitis, and two (4%) with chorioamnionitis.Three (6%) patients required blood transfusions and three (6%) had other complications, such as migraine, hypotension, and chest pain.Table 3 lists the maternal variables according to pathology.

Antepartum complications
Complications before delivery were classified into intraoperative and postoperative categories based on timing.Among 11 patients (22%), intraoperative issues were noted, with bleeding being the most common (12%), followed by procedure failure (6%), placental abruption (2%), and amniotic detachment (2%).Notably, no intraoperative complications occurred in the TTTS group, while the FETO group experienced one case (8%) of placental abruption on the day of balloon removal, while at MMC group,

Childbirth-related variables
As open fetal surgery by hysterotomy is an invasive procedure, fetoscopic surgical techniques aim to minimize surgical trauma. 13Meanwhile, following significant technical improvements and a steep learning curve for the surgical teams, fetoscopic fetal surgery is considered on par with open techniques by some researchers, although controlled head-to-head comparisons remain lacking. 3,21,22ere are few maternal complications related to fetoscopic surgeries for myelomeningocele correction, justifying the continued investment in studies focusing on this technique, which is expected to be disseminated more widely.Regarding maternal complications in our study, two (22%) patients were diagnosed with chorioamnionitis who were treated with intravenous antibiotics, and one patient (11%) required blood transfusion during pregnancy, which was not directly related to surgery but rather to the context of appendicitis during pregnancy.
In a study intended only to assess maternal complications published by Kohl et al. 23 there was no need for maternal blood transfusion, placental abruption, or spontaneous postoperative uterine contractions at immediate perioperative period; however, they described pulmonary edema in one (1.9%)patient.Nonetheless, the incidence of acute pulmonary edema described in MOMS is 6% 20 , indicating a lower risk of this complication with fetoscopic surgery.There were no cases of acute pulmonary edema in our study; however, this could have been due to the low number of cases.
Kohl et al. 23 also described the use of tocolysis for 24 h after the procedure: in two (4%) cases of chorioamniotic detachment after the procedure and in four (7.8%) patients who developed chorioamnionitis. 23In our study, all patients also underwent tocolysis for a short time, and we had one (11%) case of chorioamniotic detachment.
Despite the use of tocolysis, premature births remain problematic.Mean gestational age at delivery in our study was 33 weeks, with PPROM occurring in eight (89%) patients, which was the same gestational age described by Diehl et al. 13 in an observational study with data from 72 patients, and the same as described by Lapa et al. 3 Lapa et al. 3 described the rate of PPROM as 80%, like ours.
However, in a study published in 2021, which analyzed 170 pregnant women in eight reference centers worldwide, mean gestational age at delivery was 34.5 weeks with a PPROM rate of 67%, which decreased to 38% after modifying the technique used during the study with CO 2 humidification during fetoscopy. 12Furthermore, three neonatal deaths related to prematurity were also reported 12 , whereas in our study, there were no neonatal or intrauterine deaths related to intrauterine treatment for MMC.

CDH
5][26][27][28][29] Several observational studies have shown that FETO is associated with increased survival among children with severe pulmonary hypoplasia due to isolated left CDH; however, randomized clinical trials have not yet been published. 30e TOTAL trial was the first randomized to assess FETO, as this study was terminated early because of identification of benefits of surgery versus expectant management.From 80 patients analyzed, 40 underwent FETO and 40 maintained expectant management. 30 surgery group, median gestational age at randomization in the TOTAL trial was 27.7 weeks, and 36 (90%) patients had intrathoracic liver herniation. 30In our study, mean gestational age on the day of surgery was 28 weeks, and seven (58%) patients had intrathoracic liver herniation.
Regarding complications described at TOTAL trial related to fetal surgeries, 19 (48%) newborns were diagnosed with PPROM with a median gestational age of 32.5 weeks, one (2%) patient was diagnosed with placental abruption, one (2%) with bleeding when introducing trocater for fetoscopy, and eight (22%) with chorioamniotic detachments. 30In our study, four (33%) patients were diagnosed with PPROM, which occurred with a mean gestational age of 35 weeks.There were no cases of bleeding related to introduction of trocaters during fetoscopy or diagnoses of chorioamniotic detachment after fetoscopy, but one (8%) patient was diagnosed with placental abruption after fetoscopy was employed to attempt to remove the balloon.In this case, fetoscopy to remove the balloon was unsuccessful, and it was necessary to puncture the balloon guided by ultrasound after birth.We observed one (8%) case in which fetoscopy to remove the balloon was unsuccessful, and patient developed premature labor and fetal distress after having undergone a cesarean section, which showed the presence of a hemoamnion.In this case, balloon was removed postnatally using ultrasound-guided puncture without complications.At TOTAL trial, there was one (2%) death due to failure to remove the balloon in a patient who did not follow the recommendations and moved to a place far from the trial reference centers. 30No fetal deaths were related to balloon removal.
Mean gestational age at delivery in our population was 37 weeks, and all fetuses who underwent the procedure were born alive, with a mean birth weight of 2,560 g.Two (17%) required extracorporeal membrane oxygenation and five (42%) were discharged from the NICU.At TOTAL trial, mean gestational age at delivery was 34.6 weeks, all fetuses who underwent the procedure were born alive, mean birth weight was 2,300 g, and two (5%) required extracorporeal membrane oxygenation.Thirty (75%) patients at TOTAL trial gave birth before 37 weeks, whereas in our study, only two (17%) patients had preterm labor.
Regarding neonatal complications, at TOTAL trial, 12 (75%) newborns were diagnosed with BPD, 1 (6%) had leukomalacia, and 10 (62%) sepsis. 30In our study, two (17%) infants were diagnosed with BPD, although we had seven (58%) newborns who needed oxygen after 28 days of life, which suggests that there may have been underdiagnosed in this classification.We did not diagnose leukomalacia in our study, and nine (75%) newborns were diagnosed with neonatal infection.We also obtained two Compared to our study, mean gestational age at delivery was 31 weeks, with a mean birth weight of 1,536 g, which were similar to the results published by Gheorghe et al. 32 , Malshe et al. 33 , and Habli et al. 34 Regarding complications, at Eurofoetus study, 10 (15%) patients were diagnosed with PPROM within 28 days of the procedure and 16 (12%) fetuses were diagnosed with intrauterine death within 7 days of the procedure; in 76% of patients, at least one fetus survived. 31Malshe et al. 33 described PPROM in 32 (15.8%) cases and fetuses were born alive in 78.3% of cases.Complications in our study were observed in three (17%) patients with PPROM, and there were 10 (27%) intrauterine deaths during pregnancy, which is consistent with the results of the studies cited above. 31,33We also had three (17%) patients who experienced other complications, including one case of fetal distress, one case of fetal anemia, as well as a pregnant woman with appendicitis a few weeks after fetoscopy.
Neonatal complications were also described by Eurofoetus group: a total of 12 (8%) newborns died during the neonatal period, intraventricular hemorrhage grade III or IV was noted in two (1%) newborns, and leukomalacia in eight (6%) newborns 31 .In our group, four (15%) newborns were diagnosed with intracranial hemorrhage, but we included mild cases, not just the most severe ones; 20 (74%) newborns were discharged from NICU, with four (15%) deaths registered at neonatal period.Records of patients with leukomalacia were not available.NEC was noted in our study in four (15%) cases, which was a much higher incidence than that described by Gheorghe et al. 32 (1.8%).Malshe et al. 33 described 12 (18.5%)cases of placental abruption and four (6.2%) cases of chorioamnionitis 33 .We did not observe chorioamnionitis or placental abruption in pregnancies subjected to laser treatment for TTTS.
At Eurofoetus study, no pregnant woman died or required blood transfusion or hospitalization in the maternal ICU. 31 No deaths were observed in our study; however, three (17%) patients had infectious complications not directly related to fetoscopy, two (11%) had urinary tract infections, and one (6%) had abdominal sepsis due to appendicitis.
A retrospective study published by Habli et al. 34 evaluated 152 pregnant women who underwent laser fetoscopy to treat TTTS and the incidence of postoperative complications; 147 (97%) patients in this study underwent procedure using epidural anesthesia, while the most used anesthesia was spinal in 14 (78%).In the same study, it was impossible to complete the procedure in five patients: two cases due to peritoneal leaks and three cases due to intraamniotic bleeding from trocar introduction or laceration of the chorion plate by the laser. 34No complications were observed in our surgeries.

CONCLUSION
Our study assessed fetal surgeries performed at two reference centers for fetal medicine in Rio de Janeiro, Brazil.Fetal surgeries in Brazil play an important role, mainly because there is no possibility of pregnancy termination due to abortion.
Our study has some limitations, such as its retrospective descriptive nature based on data from medical records and the small sample size when considering the time evaluated.Analysis of less common diseases, combined with a small sample size selected for convenience through patients referred directly to the two reference centers, suggests that there is a possible selection bias, which means that our results cannot be extrapolated to other populations.
Therefore, intrauterine surgery may improve the prognosis of these fetuses; however, we cannot ignore the fact that intrauterine fetal surgeries, even minimally invasive surgeries, can result in complications in pregnant women and are associated with a higher risk of prematurity.Nonetheless, based on our findings, we conclude that intrauterine fetal surgeries are safe for pregnant women, with low morbidity, perinatal mortality, and prematurity rates, comparable to those previously reported.Premature birth remains a major problem associated with fetal surgery.

Table 1 .
Baseline characteristics of the study population

Location of placenta -no. (%)
Table 2 presents these data in detail.

Table 2 .
Fetal surgical variables

Table 3 .
Maternal complications due to fetal surgery ᵻ hypotension, ‡ chest pain and ƾ migraine TTTS: twin-twin transfusion syndrome; CHD: congenital diaphragmatic hernia; MMC: myelomeningocele Patientswith TTTS had a mean gestational age at delivery of 31 weeks, with 96% live births.Among CDH patients, the mean gestational age at delivery was 37 weeks, with all infants admitted to the NICU and experiencing respiratory issues.Finally, patients with MMC had a mean gestational age at delivery of 33 weeks, with 100% live births and relatively lower mortality rates.Table5describes the baseline characteristics of the study population, while Table6summarizes the outcomes of the individual characteristics of each pathology.
3,20verage, gestational age at delivery was 33 weeks, with a range of 25 to 40 weeks, resulting in 83% live births.Most newborns were admitted to the NICU, with 50% requiring resuscitation at the delivery room.Antenatal corticosteroids were administered to 76% of pregnant women.Respirator use was necessary for 48% of newborns, and surfactants were required in 19% cases.Additionally, 24% of newborns needed additional oxygen support after 28 days of life.Notably, mortality was observed in 26% of cases.3,20However,because of the open nature of this fetal surgery, these favorable outcomes occur at the expense of increased risks of uterine dehiscence and rupture, as well as other morbidities in mothers.

Table 4 .
Antepartum complications due to fetal surgery